Targeting of the CNS in MPS-IH Using a Nonviral Transferrin-α-l-iduronidase Fusion Gene Product

Abstract

Mucopolysaccharidosis type I (Hurler syndrome) is caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA), and is characterized by widespread lysosomal glycosaminoglycan (GAG) accumulation. Successful treatment of central nervous system (CNS) diseases is limited by the presence of the blood-brain barrier, which prevents penetration of the therapeutic enzyme. Given that the brain capillary endothelial cells that form this barrier express high levels of the transferrin receptor (TfR), we hypothesized that the coupling of IDUA to transferrin (Tf) would facilitate IDUA delivery to the CNS. A plasmid bearing a fusion gene consisting of Tf and IDUA was constructed which, when delivered in vivo, resulted in the production of high levels of an enzymatically active protein that was transported into the CNS by TfR-mediated endocytosis. Short-term treatment resulted in a decrease in GAGs in the cerebellum of mucopolysaccharidosis type I (MPS I) mice. This approach, therefore, represents a potential strategy for the delivery of therapeutic enzyme to the CNS.

Therapies for the bone in mucopolysaccharidoses

“…Here we summarize the recent achievements for bone lesions in gene therapies of animal models of MPS. [115,116], sleeping beauty transposon [117,118], gamma-retrovirus [58,[119][120][121], lentivectors [122], and adenoassociated virus (AAV) vectors [123,124]. Non-viral vectors (i.e.…”

Nanotechnology applied to treatment of mucopolysaccharidoses

“…The binding of Apo E, transferrin, insulin, or antibodies against its receptors also enables a similar drug transport across the BBB [63][64][65][66][67]. In a recent study, fusion proteins comprised of lectin and human IDUA, were efficiently endocytosed into MPS I patient fibroblasts in vitro, and resulted in reduction of cellular GAG levels [68].…”

Nonviral Gene Therapy—The Challenge of Mobilizing DNA

“…Liver-directed minicircle administration was explored also for delivery of the α-L-Iduronidase (IDUA) gene for treatment of mice with mucopolysaccharidosis type 1, a lysosomal storage disease (Osborn et al 2011). Previous attempts to express the IDUA gene from plasmid DNA in mouse liver have resulted in only short-term expression in immunocompetent mice, leading to the assumption that transgene-expressing cells were eradicated by a robust immune reaction triggered by the transgenic protein (Aronovich et al 2007;Osborn et al 2008;Aronovich et al 2009). Although copy number analyses in mouse liver have indicated that neither immune-based clearance of liver cells nor the loss of vector genomes explains the loss of IDUA production, expression from plasmids as well as from minicircles was found to be compromised in immune-competent mice (Osborn et al 2011).…”